Benralizumab

Benralizumab belongs to the pharmacological class of Monoclonal antibodies. Benralizumab appears to have immunosuppressive effects.

Benralizumab, unlike IL-5 low-affinity binding ,binds to the high affinity to the domain I of the α-chain of IL-5R and blocks its signaling and the proliferation of IL-5-dependent cell lines. On the other hand, Benralizumab is an afucosylated antibody in the CH2 region which gives it a high affinity for the FcγRIIIa on natural killer cells, macrophages, and neutrophils. This binding triggers a magnified apoptosis response in eosinophils via antibody-dependent cell-mediated cytotoxicity.

Benralizumab had been approved for the treatment as well as relieving the symptoms and maintenance of episodes of eosinophilic asthma.

A 20-200 mg of Benralizumab had shown an absorption half-life of 3.6 days and a bioavailability of 58%.Benralizumab showed a volume of distribution in the range of 52-93ml/kg. As with any monoclonal IgG antibody, Beralizumab is found to be degraded by proteases widely spread in the body. For a subject weighing 70kg, the typical systemic clearance is 0.29L/day.

The common side effects associated with Benralizumab are hives, itching, and swelling. Joint pain, hoarseness,irritation, redness of the skin, tightness of the chest, troubled breathing, etc.

Benralizumab is available in the form of subcutaneous injection..Benralizumab is available in the U.S., Canada, E.U., India, Australia, and Japan.

Benralizumab belongs to the pharmacological class of Monoclonal antibodies. Benralizumab appears to have immunosuppressive effects.

Benralizumab, unlike IL-5 low-affinity binding , binds with high affinity to the domain I of the α-chain of IL-5R and blocks its signaling and the proliferation of IL-5-dependent cell lines. On the other hand, Benralizumab is an afucosylated antibody in the CH2 region which gives it a high affinity for the FcγRIIIa on natural killer cells, macrophages, and neutrophils. This binding triggers a magnified apoptosis response in eosinophils via antibody-dependent cell-mediated cytotoxicity.

Benralizumab has been approved for relieving symptoms and also for the maintenance and treatment of episodes of eosinophilic asthma.

A subcutaneous dose of Benralizumab achieves a Cmax of 82 mcg/ml and an AUC of 775 mcg day/ml.

The onset of action of Benralizumab occurs after two days of the administration, and the duration of action occurs four days.

Benralizumab can be used in the treatment of:

• Eosinophilic asthma

Benralizumab is approved for use in the following clinical indications:

• Eosinophilic asthma

Prefilled syringe:

To be administered by the registered medical practitioner or the health care provider.

Autoinjector:

1. The syringe body should be grasped to remove the prefilled syringe from the tray. The expiration date should be checked. The syringe might contain small air bubbles. The air bubbles should not be expelled prior to administration.

2. The needle cover should not be removed until it is ready to inject. The syringe body should be held, and the needle cover should be removed by pulling it straight off. The plunger or the plunger head should not be removed while removing the needle cover, or the plunger might move. In case the prefilled syringe is damaged or contaminated (for example, dropped without a needle cover in place), it should be discarded, and a new prefilled syringe should be used.

3. The skin should be pinched gently and the needle should be inserted at the recommended injection site (i.e., upper arm, thigh, or abdomen).

4. All of the medication should be injected by pushing in the plunger all the way until the plunger head is completely between the needle guard activation clips, as this is necessary to activate the needle guard.

5. After injection, the pressure should be maintained on the plunger head and the needle should be removed from the skin. The pressure on the plunger is released on the plunger head to allow the needle guard to cover the needle. The prefilled syringe should not be recapped.

6. The used syringe should be discarded into a sharps container.

Subcutaneous injection: 30mg

Subcutaneous injection.

Maintaining health and cessation of smoking are a must.

Caffeine should be limited to use or avoided as it may lead to the risk of nervousness, rapid heartbeat, nausea, palpitations, etc.

Patients with an underlying liver disorder or liver dysfunction must avoid drinking alcohol.

A diet containing food with high sugar content and carbohydrates should be restricted. This includes pies, cakes, honey, cookies, jams, candies, chips, and bread. It is also advised to reduce or limit the intake of cholesterol and saturated fat and instead choose poultry, lean meat, or fish.

The dietary restrictions need to be individualized as per the patient's requirements.

Benralizumab may be contraindicated under the following conditions:

• Hypersensitivity to the ingredients of the medication

The treating physician should be closely monitoring the patients and keep pharmacovigilance as follows:

Hypersensitivity Reactions: Hypersensitivity reactions such as anaphylaxis, angioedema, urticaria, rash, had occurred following the administration of Benralizumab. These reactions generally are found to occur within hours of administration but in some instances, had a delayed onset i.e., within days. In the event of a hypersensitivity reaction, it is advised that Benralizumab should be discontinued. Acute Asthma Symptoms or Deteriorating Disease Benralizumab should not be used for the treatment of acute asthma symptoms or acute exacerbations. Do not use Benralizumab for the treatment of treat status asthmaticus or acute bronchospasm. It is advised that the patients should seek medical advice if their asthma goes uncontrolled or worsens after initiation of treatment with Benralizumab.

Reduction of Corticosteroid Dosage: Does not discontinue inhaled or systemic corticosteroids abruptly upon initiating of therapy with Benralizumab. Its is advised that the reductions in corticosteroid dose, if appropriate and this should be gradual and should be performed under the direct supervision of a medical physician. Reduction in corticosteroid dose might be associated with systemic withdrawal symptoms and/or unmask conditions which are previously suppressed by systemic corticosteroid therapy.

Parasitic (Helminth) Infection: Eosinophils might be involved in the immunological response to some of the helminth infections. Patients with known helminth infections had been excluded from participation in clinical trials. It is unknown if Benralizumab will influence a patient's response against helminth infections. The patients with pre-existing helminth infections should be treated before initiating therapy with Benralizumab. If patients get infected while receiving treatment with the medication Benralizumab and do not respond to anti-helminth treatment,the treatment with Benralizumab should be discontinued until the infection resolves.

Avoid alcohol usage while on Benralizumab medication as alcohol can worsen the effects of any other underlying disease condition, including conditions such as blurred vision, dizziness, etc.

There is found to be no information regarding the presence of benralizumab in human or the animal milk.The effects of benralizumab on the breastfed infant as well as on milk production are unknown. However, benralizumab is a humanized monoclonal antibody which is (IgG1/κ-class), and immunoglobulin G (IgG) is found to be present in human milk in small amounts.The health benefits and developmental of breastfeeding should be considered along with the mother's clinical need for the drug benralizumab and any potential adverse effects on the breastfed child from benralizumab or from the underlying maternal condition.

Teratogenic Effects: Pregnancy Category: not assigned by FDA

The clinical data on pregnancy exposure from the clinical trials are found to be insufficient to inform on drug-associated risk during the pregnancy.Benralizumab are said to be transported across the placenta to the fetus during the third trimester of pregnancy , therefore, potential adverse effects on a fetus are more likely to be greater during the third trimester of pregnancy. In a prenatal as well as postnatal development study conducted in cynomolgus monkeys, there was found to be no evidence of fetal harm with Intravenous administration of benralizumab throughout pregnancy at doses that have produced exposures up to approximately three hundred and ten times the exposure at the maximum recommended human dose of 30 mg Subcutaneous . In the U.S. general population, its is reported that the estimated background risk of major miscarriage and birth defects in clinically recognized pregnancies is found to be 2% to 4% and 15% to 20%, respectively

There has been found to be no sufficient scientific evidence traceable regarding the safety and use of Benralizumab in concurrent use with any particular food.

The adverse reactions related to Benralizumab can be categorized as:

Less Common

• Stiffness
• Swelling
• Fast heartbeat.
• Hives
• Itching
• Skin rash.
• Hoarseness
• Irritation.
• Joint pain
• Swelling of the lips, hands, eyelids, face, or feet
• Troubled breathing
• Troubled swallowing

Rare

• Cough
• Dizziness
• Puffiness
• Unusual tiredness
• Weakness

No formal drug interaction studies had been conducted.

The common side effects of Benralizumab include the following:

• Stiffness
• Swelling
• Fast heartbeat.
• Hives
• Itching
• Skin rash.
• Hoarseness
• Irritation.
• Joint pain
• Swelling of the lips, hands, eyelids, face,or feet
• Troubled breathing
• Troubled swallowing

Pregnancy

Teratogenic Effects: Pregnancy Category: not assigned by FDA

The clinical data on pregnancy exposure from the clinical trials are found to be insufficient to inform on drug-associated risk during the pregnancy.Benralizumab are said to be transported across the placenta to the fetus during the third trimester of pregnancy , therefore, potential adverse effects on a fetus are more likely to be greater during the third trimester of pregnancy. In a prenatal as well as postnatal development study conducted in cynomolgus monkeys, there was found to be no evidence of fetal harm with Intravenous administration of benralizumab throughout pregnancy at doses that have produced exposures up to approximately three hundred and ten times the exposure at the maximum recommended human dose of 30 mg Subcutaneous . In the U.S. general population, its is reported that the estimated background risk of major miscarriage and birth defects in clinically recognized pregnancies is found to be 2% to 4% and 15% to 20%, respectively

• Nursing Mothers

There is found to be no information regarding the presence of benralizumab in human or animal milk.The effects of benralizumab on the breastfed infant as well as on milk production are unknown. However, benralizumab is a humanized monoclonal antibody which is (IgG1/κ-class), and immunoglobulin G (IgG) is found to be present in human milk in small amounts.The health benefits and developmental of breastfeeding baby should be considered along with the mother's clinical need for the drug benralizumab and any potential adverse effects on the breastfed child from benralizumab or from the underlying maternal condition.

• Pediatric Use

There were about 108 adolescents who were aged 12 to 17 with asthma enrolled in the Phase three exacerbation trials (Trial 1: n=53, Trial 2: n=55). Out of these, 46 jad received placebo, 40 had received Benralizumab every four weeks for three doses, followed by every eight weeks thereafter, and twenty two received Benralizumab every four weeks. Patients were required to have a history of two or more asthma exacerbations requiring oral or systemic corticosteroid treatment in the past twelve months as well as reduced lung function at baseline i.e.pre-bronchodilator FEV1 less than 90%, despite regular treatment with medium or high dose LABA and ICS with or without OCS or other controller therapy. The pharmacokinetics of benralizumab in adolescents aged 12 to 17 years were found to be consistent with adults based on population pharmacokinetic analysis as well as the reduction in blood eosinophil counts was found to be similar to that observed in adults following the same Benralizumab treatment. The adverse event profile in adolescents was found to be generally similar to the overall population in the Phase three studies. The safety and efficacy in patients younger than twelve years of age have not been established.

• Geriatric Use

Out of the total number of patients in clinical trials of benralizumab,about 13% (n= 320) were aged 65 and over, while 0.4% (n=9) were aged 75 and over. There was found to be no overall differences in effectiveness or safety between these older patients as well as in the younger patients, and other reported clinical experience had not identified differences in responses between the older as well as younger patients, but a greater sensitivity of some older individuals might not be ruled out.

Physicians should be vigilant and knowledgeable about the treatment pertaining to the treatment and identification of overdosage of Benralizumab.

Doses up to 200 mg of Benralizumab were administered subcutaneously in clinical trials to patients suffering from eosinophilic disease without evidence of dose-related toxicities.

There is found to be no specific treatment for an overdose with benralizumab. If overdose occurs, it is advised that the patient should be treated supportively with some appropriate monitoring as necessary

Pharmacodynamics

Eosinophils are said to be the key target of inflammatory respiratory diseases, and they are said to undergo apoptosis in the absence of IL-5. Therefore, benralizumab action on the IL-5 receptor in basophils and eosinophils produces the apoptosis and its significant reduction in the blood.On the other hand, Benralizumab binding to natural killer cells FcγRIIIα receptor produces a direct antibody-dependent cell-mediated cytotoxicity. All these effects produce a reduction in eosinophil count in airway mucosa, submucosa, sputum, blood and bone marrow.

Pharmacokinetics

• Absorption

After the subcutaneous administration to patients with asthma, the absorption half-life was found to be approximately 3.6 days. Based on the population pharmacokinetic analysis, the estimated absolute bioavailability was found to be approximately 58% and there was found to be no clinically relevant difference in relative bioavailability in the administration to the abdomen, thigh as well as the arm. A oral dose of 16mg Benralizumab diacetate is said to reach a Cmax of 5.33±1.55ng/mL while the Tmax of 1.86±0.47h and an AUC of 32.7±9.9ng*h/mL.

• Distribution

Based on the population pharmacokinetic analysis, central as well as the peripheral volume of distribution of benralizumab was found to be 3.2 L and 2.5 L, respectively, for a 70kg individual.

• Metabolism

Benralizumab is said to be a humanized IgG1 monoclonal antibody that is found to be degraded by proteolytic enzymes which are widely distributed in the body and are not restricted to hepatic tissue.

• Elimination

From the population pharmacokinetic analysis, benralizumab is found to exhibit linear pharmacokinetics and tehre was foudn to be no evidence of target receptor-mediated clearance pathway. The estimated typical systemic clearance for benralizumab was found to be 0.29 L/d for a subject weighing 70kg. After the subcutaneous administration, the elimination half-life was found to be approximately 15 days.

1. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761070s000lbl.pdf
2. https://ec.europa.eu/health/documents/community-register/2018/20180108139598/anx_139598_en.pdf
3. https://go.drugbank.com/drugs/DB12023
4. https://www.mayoclinic.org/drugs-supplements/benralizumab-subcutaneous-route/side-effects/drg-20406682
5. https://www.drugs.com/sfx/fasenra-side-effects.html
6. https://www.fasenra.ca/?gclid=CjwKCAiAzKqdBhAnEiwAePEjktnPGJW7QU3pWkdUq4FdHUsecemMamFkwKOpyqS39g22685w2C788BoCeisQAvD_BwE
7. https://www.mayoclinic.org/drugs-supplements/benralizumab-subcutaneous-route/side-effects/drg-20406682?p=1